Elucidating Nmda Receptor Hypofunction Using Simultaneous Eeg-Fmri Measures of Ketamine-Induced Neural Dynamics

Background Glutamatergic signaling deficits, particularly involving N-methyl-D-aspartate (NMDA) receptors, are increasingly recognized as central to the complex pathophysiology of schizophrenia. The resulting imbalance between excitatory and inhibitory neurotransmission is emerging as a critical therapeutic target. While ketamine exposure in healthy volunteers provides a window into NMDA receptor hypofunction, reliable markers are needed to assess the severity of this dysfunction and to guide interventions aimed at restoring neural balance. Recent evidence suggests that modulations in low gamma frequency EEG activity (30-50 Hz) during cognitively demanding auditory tasks may serve as a promising indicator of underlying NMDAR signaling. Aims & Objectives By simultaneously combining EEG and functional MRI (fMRI) in a single experimental setting, our study aims to investigate ketamine-induced changes in neural activity and to examine whether glycine, an NMDA receptor co-agonist, can modulate these shifts. This work may help refine markers to personalize treatment strategies in conditions associated with NMDA receptor dysregulation. Method Thirty-two healthy subjects participated in a placebo-controlled, longitudinal study. Each underwent three separate sessions: a baseline assessment under placebo, and two subsequent sessions with ketamine administration preceded by either intravenous glycine or additional placebo. The order of pretreatment was randomized, with sessions separated by at least 1 week. During each visit, participants performed an auditory choice response task while EEG and fMRI data were simultaneously collected to capture both electrophysiological signatures and hemodynamic responses. Statistical analyses employed linear mixed models (sociodemographic and behavioral data), accounting for relevant covariates such as age and cannabis use, cluster-based permutation tests (EEG), and generalized linear models (fMRI). Results Acute ketamine exposure produced significant schizophrenia-like symptoms, as indicated by higher Positive and Negative Syndrome Scale (PANSS) scores (p < 0.01) and increased error rates (p = 0.03) and response latencies (p = 0.01) in the auditory task. At the same time, fMRI signals from attention-related networks were reduced (cluster-level FDR correction p < 0.05), while EEG recordings showed a decrease in evoked low gamma activity (p < 0.01). In contrast, when glycine was administered before ketamine, it modulated these neural and behavioral effects. While the fMRI response was not affected, glycine pretreatment attenuated ketamine-induced performance deficits regarding response latencies (no significant difference between glycine pretreatment and baseline) and partially restored gamma-band activity (p < 0.01). Discussion & Conclusions Our findings support the idea that combined EEG-fMRI monitoring during ketamine challenge provides a valuable window into NMDA receptor functionality. The observed gamma-band changes, together with behavioral responses, suggest that glycine's effects on these neural signatures may inform more individualized approaches to the treatment of conditions characterized by NMDA receptor hypofunction. In particular, the glycine-related effect supports the notion that EEG-derived gamma metrics are sensitive to shifts in the balance of excitatory and inhibitory drive at the NMDA receptor level. These integrative biomarkers hold promise for guiding future therapeutic strategies and advancing our understanding of how targeted interventions can recalibrate glutamatergic circuits implicated in schizophrenia and related disorders.